Ionically bonded block elastomeric copolymers of a polyquaternary polyurethane and heparin

ABSTRACT

A neutral elastomer is prepared by the urethane linking reaction of diisocyanates with tertiary amino diols. The neutral elastomer is quaternized and is then reacted with an anionic polymer such as heparin to form ionically bonded block elastomeric copolymers. The heparin copolymer has non-thrombogenic characteristics. It can be dissolved in solvents and utilized to form a non-clotting coat on the blood lines in kidney machines.

United States Patent [1 1 Yen et al.

[ IONICALLY BONDED BLOCK ELASTOMERIC COPOLYMERS OF A POLYQUATERNARYPOLYURETHANE AND HEPARIN [75] Inventors: Shlao-Ping Siao Yen; AlanRembaum, both of Altadena, Calif.

[73] Assignee: California Institute of Technology, Pasadena, Calif.

[22] Filed: Aug. 14, 1970 [2!] Appl. No.: 63,722

7/l969 Bennett et al. 424/183 OTHER PUBLlCATlONS Chem. Abst. 73:7l93f,Rembaum et al., Synthesis-- [451 Aug. 28, 1973 Elastomers.

Rubber Chemistry and Technology, Vol. 39, 1966, pp. 1288-1292, FALB etal., Elastomers in the Human Body.

Battelle Memorial institute, PB 168861, June 29, 1965, Published Mar.10, 1966, FALB et al., Development of Blood-Compatible PolymericMaterials" pp.(col.) l-l 1.

Primary Examiner-William H. Short Assistant Examiner-Edward WoodberryAttorney-Lindenberg, Freilich and Wasserman [5 1' ABSTRACT A neutralelastomer is prepared by the urethane linking reaction of diisocyanateswith tertiary amino diols. The neutral elastomer is quatemized and isthen reacted with an anionic polymer such as heparin to form ionicallybonded block elastomeric copolymers. The heparin copolymer hasnonthrombogenic characteristics. it can be dissolved in solvents andutilized to form a nonclotting coat on the blood lines in kidneymachines.

12 Claims, 2 Drawing Figures IO I l l G! C O |O I) I I) O O E j 8QUATERNIZED g IO NOT HEPARINIZED J C! O p- ]0 i l i l 40 8O l2O I80TEMPE RATURE C TORSI ONAL MODULUS, dyne/cm PATENTEDmczs I973 FIG. I

TORSIONAL MODULUS, dyne/ cm QUATERNIZE D H EPARINIZED BEFORE HEATING I ll l I I -loo 0 40 80 I80 TEMPERATUREfC IO" 1 I I I F I I I I I IHEPARINIZED IO l0 FIG 2 QUATERNIZEDJ 10 NOT HEPARINIZED INVENTORS.SHlAO-PING SIAO YEN ALAN (NMI) REMBAUM 7 BY [0 l l. l l I I I I 0 40 so120 TEMPE RATUREIC I80 f sl zp l AT TORNEYS.

IONICALLY BONDED BLOCK ELASTOMERIC COPOLYMERS OF A POLYQUATERNARYPOLYURETHANE AND HEPARIN ORIGIN OF THE INVENTION The invention describedherein was made in the performance of work under a NASA contract and issubject to the provisions of Section 305 of the National Aeronautics andSpace Act of 1958, Public Law 85-568 (72 Stat. 435; 42 USC 2457).

BACKGROUND OF THE INVENTION 1. Field of the Invention:

The present invention relates to cationic elastomeric polymers and blockpolymers thereof with an anionic macromolecular material such asheparin.

2. Description of the Prior Art:

Several classes of polyelectrolytes have recently been synthesized inwork related to preparation of semiconducting polymers. Polyelectrolytesknown as ionenes were disclosed in application Ser. No. 678,501 nowabandoned. The ionenes were prepared by linking reactions of organodihalides with ditertiary amines to form essentially linear polymerscontaining the quaternary nitrogen atom within the polymer chain. Linearpolymers of widely varying properties were obtained.

Cationic viscoelastic linear ionene polymers were disclosed inapplication Ser. No. 825,489, filed May I 9, I969, now U.S. Pat. No.3,655,814, issued on Apr. ll, 1972. These polymers were prepared bylinking reactions between monomeric starting materials, preferably ofprepolymer magnitude containing quaternary nitrogen forming coreactantsand condensation residue forming coreactants, preferably urethaneforming moieties.

It has been found that the quaternary center within the chain of theselinear ionenes is excessively sterically hindered and forms weakcomplexes with anionic materials. Solvation of the quaternary center canweaken the mechanical properties of the polymers and may even result infracture of the chain.

There is a particularly urgent need for polymeric complexes of heparinthat can be fabricated by conventional coating, casting and moldingtechniques. The bonding of heparin to polymers constitutes one of themost promising approaches to the development of blood compatiblematerials.

Heparin is a mucopolysaccharide acid occuring in various animal tissues.Specifically, it is a glucuronic acid glucoside and is used medicinallyin the form of a sodium salt. Heparin renders blood incoagulable, mostprobably by interfering with the formation of intrinsic thromboplastinand the action of thrombin.

Ionic complexes of heparin with linear ionenes have been found togradually lose ionic bonded heparin during use with the resultantcoagulation of lipid materials on the surface of the polymer in contactwith blood.

SUMMARY OF THE INVENTION In accordance with the invention a new class ofelastomeric ionic block polymers have been synthesized.

The novel polymers have the formula:

where R and R are organic groups which may be of prepolymer length, R isa short chain hydrocarbyl linking chain and R R and R are hydrogen orthe same or different lower aliphatic or aromatic groups. Z and Y arecoreactive condensation groups, ZY is the residue of the condensation ofZ and Y, n is an integer greater than 2; preferably 10 to 1,000 or more,and A is an anion, suitably halo.

The cationic viscoelastic polymer materials in accordance with theinvention have an even distribution of residual negative chargethroughout the polymer matrix, and a high concentration of intraandintermolecular pseudo cross links. The flexible polymeric chains arecapable of shielding positive charges and this prevents bonddissociation. Solvation of the pendant side chains containing thequaternary groups does not detrimentally affect the mechanicalproperties to the same extent as in linear polyurethanes. The pendantcationic groups are better exposed and are more avilable for ioniccross-linking with material such as dibromides. Furthermore, byutilizing polymerization conditions described below, the polymers areprepared in high molecular weight.

Cationic viscoelastic materials according to the invention will findmany uses. The presence of cationic charge in the polymer willcontribute conductivity to the product which can be further enhanced bycomplexing the cationic centers with charge-transfer complexing agents,such as TCNO. Maten'als having conductivity within the semi-conductorrange can be used in printed circuits and other electronic devices,Films of these materials would find application in forming ,ehargedmaster plates for graphic reproduction and uland fungicidal activity.Therefore, surgical devices or articles such as tubing or gloves, formedof materials having these properties would be inherently germicidal aswell as resistant to build up of static-electrical charges. In addition,by using well specified prepolymers, the polymerimtion product may beused in flocculation of impure water.

The block polymeric viscoelastic complexes with heparin, form anon-thrombogenic material that can be used to form the surfaces ofprosthetic devices or articles in contac with blood. The block polymercan be used to coat the insides of tubes utilized in kidney dialysismachines or heart-lung machines or to coat the inside and outside ofcatheter surfaces to keep them free from clotting if present in a bloodvessel for a long period of time. THe block polymeric non-thrombogenicmaterial can also be used to impregnate Dacron, (polyester) sleeves usedas artificial arteries.

These and many other attendant advantages of the invention will becomeapparent as the description becomes better understood by reference tothe following detailed description when considered in conjunction withthe accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a graph of shear modulusversus temperature for the polyelectrolyte elastomers of Examples 2 and12.

FIG. 2 is a graph of shear modulus versus temperature for thepolyelectrolyte elastomer of Examples 4 and 13.

DESCRIPTION OF THE PREFERRED EMBODIMENTS -Z general reaction synthesisaccording to the invention comprises reaction of a compound of theformula:

Z-R (II) or Z-R -Y (III) with a compound of the formula:

to form an intermediate non-charged or neutral polytertiary aminopolymer of the formula:

l Rial.

where R, R,, R R and R and n have the abovedefined meanings.

' The polymer is then reacted with a quatemizing reagent of the formula:

RgA

i type of prepolymer.

The Z and Y groups are selected from condensation coreactants generallyutilized in forming condensation resins such as isocyanate-hydroxy](urethane) isocyanate-amine (urea), hydroxyl-carboxyl (polyester)amino-carboxyl (amide) and the like. Urethane linking reactants arepreferred due to the ready availability of diverse polyisocyanatematerials, the absence of elimination products and the ready ability toselect and control the properties of the final prepolymer.

Examples of suitable monomeric polyisocyanates includebenzene-l,3-diisocyanate, hexane-1,6- diisocyanate,tolylene-2,4-diisocyanate (TDI), tolylene-2,3-diisocyanate,diphenylmethane-4,4- diisocyanate, naphthalene 1,5-diisocyanate,diphenyl- 3,3'-dimethyl 4,4'-diisocyanate,diphenyl-3,3'-dimethoxy-4,4'-diisocyanate diethyl ether,3(diethylamino)- pentane-1,5-diisocyanate, butane-1,4-diisocyanate,cyclohex-4-ene-l,Z-diisocyanate, benzene-1,3,4- triisocyanate,naphthalene-1,3,5,7-tetraisocyanate, naphthalene-1,3,7-triisocyanate,toluidine-diisocyanate, isocyanate terminated prepolymers, polyarylpolyisocyanates, and the like. A suitable commercially availablepolyaryl polyisocyanate is a polymethylene polyphenyl isocyanate knownas PAPl-l (The Carvin Co.). This material has an average of 3 isocyanategroups per molecule and an average molecular weight of about 380.

Other commercially available higher molecular weight liquidpolyisocyanates are Adiprene L-l00 (DuPont) an isocyanate terminatedpolybutylene oxide having a molecular weight of about 2,000, AdipreneL-167 (DuPont) an isocyanate terminated polybutylene oxide having amolecular weight of about 1,350. Multrathane-242F (Mobay) a polyesterterminated with isocyanate groups and Solithane 113 (Thiokol) which is atriisocyanate derivative of glycerol and ricinoleic acid.

Terminally reactive liquid polymers such as hydroxy terminatedpolybutadienes containing 20 to 500 or more carbon atoms or Bis-phenol Aterminated liquid polysiloxanes can be converted to diisocyanates byreaction with a diisocyanate such as hexa-methylene diisocyanate. As thecarbon length of the prepolymer increases, elastomeric properties arefavored.

The R group in the monomeric compounds of Formulas III and IV may alsobe aliphatic, aromatic or the various prepolymers discussed above. Inthe case of the use of a prepolymer diisocyanate the hydroxy aminematerial is suitably a compound of the formula:

where R, and R are lower alkyl, aryl such as phenyl, aralkyl such asbenzyl or lower alkenyl, and m is an integer from 0 to 5. Exemplarycompounds are 3-dimethylamino-l,2,-propane diol, 4-diethylamino-l,3-butane diol, 6-dimethylamino-1,4-hexane diol.

In the quaternizing reagent R A, R, may be hydrogen, lower alkyl, arylsuch as phenyl, aralkyl such as benzyl or alkenyl and A may be halo suchas chloro, boromo or iodo, alkyl sulfate such as methylsulfate or alkyliodide such as methyl iodide.

The polymerization reaction may be conducted in bulk or in the presenceof a solvent for the monomers and polymer product such as benzene. Thereaction EXAMPLE 1 100 grams of Adiprene L167 (6.15 to 6.55% NCO) wasreacted with 9.4 grams of vacuum distilled 3-dime- 5thylamino-1,2-propane diol at C for 24 hours. The

reaction was followed by means of l.R. spectra. The disappearance of theOH peak at A 3480 cm as well as the NCO absorption peak at A 2,280cmindicated completion of the reaction. After cooling to roomtemperature, the solid polymer was dissolved in benzene and precipitatedwith a tenfold volume of methanol. The purified polymer was dried in avacuum oven overnight at 50 C.

The amount of diol utilized is calculated from the NCO analysis asfollows:

Grams diol [(%NCO)(Wt. of NCO compd)(MW Diol)]/[(2)(MW NCO)] where:

% NCO is the analyzed weight content of isocyanate MW Diol 119 for thisexample MW NCO 42 EXAMPLE 2 100 grams of the product of Example 1 wasdissolved in tetrahydrofuran (TI-1F) to form a solution. A concentratedsolution of HCl g of 37-38% HCl by weight) was added corresponding to a100% stoichiometric excess. The solution was stirred at room temperatureovernight before it was precipitated with a tenfold volume of n-hexane.It was then washed thoroughly with water to remove unreacted HCl. Thequaternized polymer was dried in vacuum at 50 C overnight.

The quatemizing reagent, in this case BC]; is present in at least a 100%excess and preferably at least four times the stoichiometric amount isprovided as follows:

Volume of I-ICl [4 (Moles l-lCl (MW I-ICl]/[(Density I-ICI) (Wt% HCl)]where moles of HCl is equal to the moles of diol.

EXAMPLE 3 EXAMPLE 3A Example 3 was repated in 10% benzene solution atreflux for 48 hours to form a polymer product. The solvent was removedby freeze drying.

EXAMPLE 4 The polymer product of Example 3 was quaternized in accordancewith the procedure of Example I to form a quaternized polymer, (chloridecounterion).

EXAMPLE 5 Dihydroxypolybutadiene (55g) of equivalent weight of 1,100dissolved in benzene (150cc) was added to 1,6-hexamethylene diisocyanate(8.4g) in dry benzene (5000) and heated to 70 C. The reaction wasmonitored by means of I.R. as described in Example '1. At thecompletions of the above reactions, freshly distilled3-dimethylamino-l,2-propane diol (2.96g) was added to the mixture atroom temperature and this reaction was completed within 24 hours.Methanol (11) was then added to precipitate the product. The solventswere then decanted and the residual solvents were removed by vacuumevaporation. The thus prepared polymer was quatemized as described inExample 2.

EXAMPLE 6 3-dimethylamino-1,3-propane diol (295g) in dry benzene (15cc)was added to 1,6-hexamethylene diisocyanate (4.205g) in dry benzene(15cc) and left standing at room temperature for 3 days. Tetrahydrofuran(50ml) was first added to the reaction mixture followed by concentratedhydrochloric acid (50c). After thorough mixing, the supernatant liquidwas decanted, the residue was washed with THE (20cc) and dried in avacuum oven. Yield of quaternized polymer 6.5g.

The quaternized polymer (0.9g) dissolved in water (20cc) was added to anaqueous solution of sodium heparin (0.5g in 10cc of water) a precipitateof a heparin complex was immediately formed. The complex was stirredwith acetone (three times), subsequently with water (three times). Afterfiltration and drying a white crystalline product 1.2g) was obtained.The analysis of S showed approximately 44% of heparin in the complex.

EXAMPLE 7 720 gm. of Adiprene L-l67 (DuPont-6.38% NCO) was reacted atreflux with 65.2 gm. (0.54 mole) of dimethylaminopropanediol in 3,000 mlbenzene in a flask immersed in an oil bath. The reaction was carried outunder a gentle flow of nitrogen. Reflux temperature was approximately Cwhile maintaining an oil bath temperature of -l 10 C. v

The extent of reaction is dependent on time of reaction and uponconcentration of reactants. The extent of reaction was monitored by theNCO stretching frequency of the Infrared spectra. The absorption at A(NCO), A (OH) and A (NH) were monitored. The ratio A A should approachzero as the reaction of NCO proceeds. The results are presented in thefollowing table.

TABLE 1 RATIO OF ABSORPTION AT ABSORPTION WAVELENGTHS (MICRONS) TIME hlk A A STATE 19 hr. 0.33 0.50 Viscosity increasing but flows easily. 4]hr. 0.36 0.24 Viscosity still increasing. 65 hr. 0.22 0.17 Very viscous.Heavy Foaming. 65 hr. 0.0 .0.0 (quenched 2 hr. withdimethylaminoethanol) The IR. spectrum showed an absorption ratio of h mof 1.7. This corresponds to a peak molecular weight of 112,000 as laterdetermined by Gel Permeation Chromatography, (GPC) based on apolystyrene calibration curve.

At the end of the reaction period, the solvent was distilled directlyfrom the oil bath (approximately 3 liters was collected). This procedureis suitable for lower molecular weight (MW) material. For higher MWmaterials, the extent of foaming is too great. In this case, the polymeris poured while still warm into a Teflon, (polytetrafluoroethylene)lined pan and air dried. Only a slight amount of bubbling in the polymerwas noted at this time. N-Hexane was added to approximately the 4 litermark. This insoluble mixture was stirred and decanted to remove lower MWmaterial. The remaining polymer was dried using the same flask and oilbath with a vacuum pump and liquid N trap. The polymer will fluff due tofoaming.

7 EXAMPLE 3 Approximately 1,000 cc of Tetrahydrofuran was added to 200gm of the fluffed" polymer. Constant stirring was necessary to bring thpolymer back into solution. 84.5 cc of HCl solution, (four timesstoichiometric amount) was added slowly. The solution was cloudyinitially, but further addition of l-lCl cleared the solution. Stirringwas continued overnight. The quaternized polymer in THF was poured into5 gal. of distilled water. This precipitation process was continueduntil all the polymer was collected. Drying was accomplished in a vacuumover with trap at room temperature[ GPC MW 68,500

The volume ratio is preferably maintained below to minimize the effecton MW. High MW polymer may not dissolve easily into THF, but willprecipitate out without salting. Low MW polymer will dissolve easilyinto THF, but may have to be salted out from water.

The quatemized elastomeric polymer are further reacted according to thisinvention with anionic polymers or salts thereof such as polystyrenesulfonate, polyacrylates and the like and particularly with heparin orits alkali metal or ammonium salts to form viscoelastic ionically linkedblock polymeric salts.

The heparin content of the block polymer can be varied between 5% toabout 20% by weight. Higherheparin content materials can be prepared.However, the latter have a lower degree of elasticity. Lower heparincontent materials are soluble in common organic solvents while materialscontaining above heparin are soluble in polar solvents-such as THF,dimethylformamide (DMF), hexamethyl phosphoramide (Hexametapol) andespecially mixtures thereof with l-methyl-Z-pyrrolidone. For the highestheparin content materials a small amount of about 0.01% to 5% of aprimary or secondary amine such as heptylamine in DMF is necessary toachieve complete solubility.

The block polymer forms by ionic reaction of the quatemized elastomer,(chloride counterion), with sodium heparin with elimination of sodiumchloride. Hence, the amount of chloride after reaction is very low. Thereaction is conducted simply by combining the elastomer with sodiumheparin preferably as separate solutions in solvent, suitably in 50:50by volume mixtures of methanol and water.

In order to prevent clotting of blood, the ratio of heparin to polymeris preferably in excess of twice the amount necessary to satisfy the netnormalized positive charge of the polymer. For example, the polymer ofExample 8 has a normalized charge of l per 1,450 gm. Heparin has a netnormalized negative charge of 1 per 143 gm. A minimum weight ratio of2X143/l,450 or about 20% is necessary. An example prepared at a ratio of25% follows.

EXAMPLE 9 gm of the quatemized polymer of Example 8 was dissolved inmethanol (1,700cc). After the polymer dissolved, 1,700 cc of water wasslowly added to form a 50:50 water-methanol mixture.

32.5 gm of sodium heparin was dissolved in 400 cc of water. Another 400cc of methanol was slowly added to make a 50:50 water-methanol mixture.

The heparin solution (conc.-4%) was added to the polymer solution(conc.-4%) after filtration of both solutions. The mixtures were addedquickly and totally with constant vigorous stirring. The weight ratio ofheparin to polymer was 25%.

The resulting precipitate was collected, washed with water and vacuumdried at room temperature. A portion remained in solution and was saltedout with 1,000 ml of a 10% Na,Cl solution.

A film pressed from this material and exposed to plasma did not causeclotting. The ratio was reduced to 10% heparin which would leave nonegative charges available. A film pressed from the latter materialclotted plasma in a normal time period.

EXAMPLE 10 The quatemized L167 polymer (40 gm) of Example 2 wasdissolved in methanol (500 cc). Distilled water (500 cc) was added tothe mixture slowly with stirring. The solution remained homogenous.(solution 1). Sodium heparin (8 gm) was dissolved in distilled water(200 cc). Slow addition of methanol (200 cc) followed with stirring. Ahomogenous solution of heparin was obtained (Solution 2). Solution 2 wasadded to Solution 1 to yield a block copolymer of low heparin content.

EXAMPLE 1 1 Addition of Solution 1 to Solution 2 yielded a blockcopolymer of much higher heparin content.

EXAMPLE 12 8 gm of Solution 2 of heparin was added to a Solution 1 ofquatemized L-l00 polymer (40 gm) of Example 4 to form a low heparincontent copolymer.

EXAMPLE 13 The reverse order of addition was followed and a heparinblock copolymer of higher heparin content re sulted.

The results of quantitative determination of chloride and heparincontent of the Adiprene series of copolymers as well as the solubilityof the elastomers before and after reaction are recorded in Table 2.

TABLE 2. 611121110111. ANALYSIS AS113 sbt'tmnw Percent Cl Percent Anion1 to cation Example Matensl Theor. Exp. S Heparin Solubility ratio 1Neutral Benzene, T1115, etc 2 Quaternized 2.40 2.40 0 CHJOH,CH3OH/H10,THF 11 Hepannized. 0.0 0.50 1. 58 15.8 Hexametapol, methylpyrr0lidone 1. 50 10 d0 0.0 0.16 1.49 10.4 DMF, hexametapol, etc 1.42 5Neutral" Benzene, THF, etc 7. Quaterruze 1.8 1.8 0 0 CHBOH, CHZOH/HZO,THF. 13 Heparinized 0. 0 0.3 1. 04 10. 4 Hexametapol 12 "do 0.0 0.2 0.72 T. 2 DBIF, hexametapol, THF/DMF 1.16

l Anion unit segment wt. percent quatemized polymer Cation wt. percentheparin X No. of anions per unit segment of heparin No. of cations perunit segment of quatern. polymer The formation of the ionic bondsresults in the elimination of sodium chloride and the amount of residualchlorine is very low. As expected, the heparin block copolymers arecompletely insoluble in methanol, but may be dissolved in the otherlisted solvents. Normally, heparin complexes have a very limitedsolubility. The solvent system of DMF and primary or secondary aminesconstitute a special claim.

The GPC molecular distribution profile indicates that the neutralpolymer did not undergo any side reaction during quaternization. Themolecular weight of the THF soluble heparin block copolymer is about58,000. Since this molecular weight is about twice that of the neutralpolymer, it is further evidence of the ionic bonding in the complex.

The ten second shear modulus versus temperature curves (FIGS. 1 and 2)determined by means of a Gehman apparatus show a dramatic increase inmodulus of two heparin complexes as compared with the nonheparinizedmaterials. The higher modulus in the temperature range of l to 140 C(FIG. I) as well as the slope of the curve is attributed to pseudocrosslinks formed between the negative charges of heparin and positivecharges on the polymer. This type of crosslinkditional reaction istaking place on heating the complex 7 to a temperature of 60 C. This isprobably due to further reaction of unreacted anionic groups of theheparin nolecules with the residual chloride of the quaternized polymerand is consistent with the chloride analysis (0.5 wt.%), (See Table 2).

raises the modulus and this is certainly due to the occurrence ofcrosslinking. The latter is also responsible for the dramaticimprovement in tensile strength. The degree of crosslinking is alsoreflected in the anion to cation ratio. The smaller the ratio, thehigher the tensile strength (Table 3) as expected. AAs the molecularweight of unit segment increases, the number of positive chargesdecreases; therefore, the elongation at break is expected to be higherand this is also born out by the data of Table 3.

The nature of the cross-links which are due to an ionic bond between thenegative groups on the heparin molecule and the positive nitrogen on thequaternary polymer permits molding under pressure and solubility TABLE3.MECHANICAL PROPERTIES Tensile Percent strength Anion (I.S.), Elongatocation Sample Method p.s.i. tion S Remarks ratio Example 4. Quatcrnizedwithout heparin (M.,=2,000) 862 2,175 Low concentration of N Example 12.Add tion of heparin to polymer (Mn=2,000) 6,618 Increased T.S. due tocrr sslinking... Example 13 Addition of polymer to heparin (.\ln=2,000)9, 515 1,112 0.72 High concentration of crosslinks... 1.143 Example 2...Quatermzcd without heparin (M,.=1,350) 3, 054 1, 565 High concentrationof N+ Example 11. Addition of polymer to heparin (M,,=1,350) 8. 681 2321.58 Reduced concentration of crosslinks.. 1. 50

in polar organic solvents. This would of course not be true forcovalently cross-linked polymers. The block copolymer can be molded orextruded to form tubes or other shaped articles.

Films or membranes can be formed by casting a solution of the copolymerand evaporating the solvent. The surfaces of membranes, tubes,catheters, valves, prosthetic veins, etc., can be coated with solutionsof the copolymer and the solvent removed, suitably by vacuum drying todeposit a non-thrombogenic coating. The copolymer is compatible withnumerous substrates such as Tygon (polyvinyl) Teflon(polytetrafluoroethylene), Dacron (polyester), silicone resins, glass,polystyrene, and polyurethane.

EXAMPLE 14 Polyester type polyurethane tubing (1 /8 inch and 1/4 inch1-D) were coated by means of a 5% DMF heparin complex solution (16%heparin content). The surface of the coating and the longitudinal crosssection were examined by means of an electron scanning microscope. Themicrographs showed good surface homogeneity and yields a value of 28p,for the coating thickness.

A smooth coating is also obtained from the quaternized polymer withoutheparin. However, it is interesting to note that by coating the surfacewith the quaternized polymer and reacting subsequently with an aqueoussolution of heparin, a coat is obtained with numerous holes. This isalso true if a methanol-water heparin solution is used instead or purewater. The hole forma- A tion may be due to contraction of the matrixwhen TABLE 4 IN VITRO BLOOD CLOTTING TESTS (AFTER 16 HOURS WATER WASH)Time in A inch ID tube Clotting time in glass Hours Minutes 4 (1stCycle) No clot 4.5 (2nd Cycle) 19 4 (3rd Cycle) 19 24 (1st Cycle) 10TABLE 5 IN VITRO BLOOD CLO'I'IING TESTS (AFTER 24 HOURS WATER WASH) Timein K! inch ID tube Clotting time in glass Hours Minutes 4 (lst Cycle) 74 (2nd Cycle) 7 24 (lst Cycle) 6 N heparin could be detected by means ofthe Azure A dye in aqueous extracts of the heparinized copolymers. THepositive charges in the copolymers are evidently shielded by theflexible polymer chains since blood is not coagulated. This shieldingmay also contribute to the high retention of heparin. The values oftensile strength, elongation at break and shear modulus as a function oftemperature show that the heparinized complexes have good mechanicalproperties under ambient conditions. The solubility of high heparincontent complexes in polar organic solvents offers important advantagesfor fabrication applications. Molded films of heparin complexes gain upto 30% in weight when immersed in aqueous media for 24 hours. Thisindicates good permeability. The latter is also responsible foropaqueness of coatings in prolonged contact with water.

It is to be understood that only preferred embodiments of the inventionhave been described and that numerous substitutions, modifications andalterations are all permissible without departing from the spirit andscope of the invention as defined in the following claims.

What is claimed is:

1. An ionic block elastomer of the formula:

where R is lower alkylene, R is lower alkylene, R R and R are selectedfrom hydrogen and lower alkyl, R is a liquid prepolymer having amolecular weight from 1,000 to 3,000 selected from the class consistingof polyether, polyester, silicone, polyurethane, and polyamide;

Z and Y are selected from hydroxyl and isocyanate groups, ZY is theurethane residue of the condensation of Z and Y, n is an integer from 10to 1000;

and r A is heparin and the elastomer contains between 5 and 20% ofweight of heparin forming a high concentration of interandintra-molecular ionic cross links between quaternary nitrogen atomspendant from the prepolymer chain.

2. An elastomer according to claim 1 in which the heparin content isbetween 10 and 15%, and the elastomer is dissolved in a solvent selectedfrom the group consisting of polar solvents and mixtures thereof with analkyl amine.

3. An elastomer according to claim 2 in which said solvent is selectedfrom dioxane, acetone, tetrahydrofuran, dimethylforrnamide and mixturesthereof with 0.01 to 5% of a primary or secondary alkylamine.

4. An elastomer according to claim 3 in which the solvent is a mixtureof dimethylformamide and diaminoheptane.

5. A method of rendering a surface nonthrombogenic comprising coveringsaid surface with a film comprising the elastomer of claim 1.

6. A method according to claim 5 in which said surface is prepared bymolding a shaped article from said elastomer.

7. A method according to claim 5 in which said surface is formed bycasting a film of said elastomer.

8. A method according to claim 5 in which said surface is formed bycoating a substrate with a solution according to claim 2 and evaporatingthe solvent therefrom.

9. An-article of manufacture comprising a film of the ionic blockelastomer as defined in claim 1.

10. An article according to claim 9 in which the film is supported on asubstrate.

l 1. An article according to claim 10 in which the substrate is selectedfrom the group consisting of polyvinyl, polytetrafluoroethylene,polyester, silicone resins, glass, polystyrene and polyurethane.

12. An article according to claim 9 in which said film is in tubularshape.

2. An elastomer according to claim 1 in which the heparin content isbetween 10 and 15%, and the elastomer is dissolved in a solvent selectedfrom the group consisting of polar solvents and mixtures thereof with analkyl amine.
 3. An elastomer according to claim 2 in which said solventis selected from dioxane, acetone, tetrahydrofuran, dimethylformamideand mixtures thereof with 0.01 to 5% of a primary or secondaryalkylamine.
 4. An elastomer according to claim 3 in which the solvent isa mixture of dimethylformamide and diaminoheptane.
 5. A method ofrendering a surface nonthrombogenic comprising covering said surfacewith a film comprising the elastomer of claim
 1. 6. A method accordingto claim 5 in which said surface is prepared by molding a shaped articlefrom said elastomer.
 7. A method according to claim 5 in which saidsurface is formed by casting a film of said elastomer.
 8. A methodaccording to claim 5 in which said surface is formed by coating asubstrate with a solution according to claim 2 and evaporating thesolvent therefrom.
 9. An article of manufacture comprising a film of theionic block elastomer as defined in claim
 1. 10. An article according toclaim 9 in which the film is supported on a substrate.
 11. An articleaccording to claim 10 in which the substrate is selected from the groupconsisting of polyvinyl, polytetrafluoroethylene, polyester, siliconeresins, glass, polystyrene and polyurethane.
 12. An article according toclaim 9 in which said film is in tubular shape.